In vivo efficacy of zidovudine (3'-azido-3'-deoxythymidine) in experimental gram-negative-bacterial infections

Abstract

The therapeutic efficacy of orally administered zidovudine (3'-azido-3'-deoxythymidine) was determined in animals infected with Escherichia coli and Salmonella dublin. The 50% effective dose (ED50) of zidovudine (9.6 to 11.8 mg/kg of body weight) compared favorably with that of trimethoprim (19.4 to 22.2 mg/kg) in mice with systemic E. coli infection. At 50 mg/kg, both zidovudine and ampicillin reduced the number of bacteria in the kidneys of mice and prevented lethal infection in mice with ascending pyelonephritis caused by E. coli. Zidovudine prevented a lethal S. dublin infection in calves over a wide dose range (8.0 to 31.0 mg/kg per day). Zidovudine levels in plasma of uninfected mice were 28.2 ± 4.5 and 7.9 ± 2.2 ,ug/ml at 30 and 60 min, respectively, exceeding the MICs for the bacteria used in the infections. Few zidovudine-resistant strains were observed. The in vivo data raise the possibility that zidovudine may have an antibacterial effect in patients receiving this therapy.The synthetic nucleoside zidovudine (3'-azido-3'-deoxythymidine) is an antimicrobial agent with a spectrum of in vitro activity that encompasses human immunodeficiency virus (HIV) (8) AIDS, abstr. no. 556, 1985), and gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, and Haemophilus influenzae (1). Zidovudine has shown no activity against Pseudomonas aeruginosa, grampositive or anaerobic bacteria, or common pathogenic fungi (such as Pneumocystis carinii) frequently isolated from HIV-infected patients (Nusinoff-Lehrman et al., Int. Conf. AIDS, 1985). E. coli and Salmonella dublin have been shown to be exquisitely susceptible to zidovudine, with in vitro MICs in the range of 0.0025 to 0.3 ,xg/ml (Table 1).We extended these in vitro observations to determine the in vivo efficacy of zidovudine in experimental bacterial infections that included a mouse systemic E. coli infection, acute ascending E. coli pyelonephritis in mice, and S. dublin salmonellosis in calves.MATERIALS AND METHODS Antimicrobial agents. Zidovudine and trimethoprim were laboratory reference preparations (Burroughs Wellcome Co., Research Triangle Park, N.C.). Ampicillin was purchased as the sodium salt (Sigma Chemical Co., St. Louis, Mo.). For all studies on mice, compounds were dissolved or suspended just before use in an aqueous suspending vehicle consisting of 1.0% Tween 80 and 0.5% low-viscosity sodium carboxymethylcellulose (Sigma). For studies in calves, zidovudine was administered by subcutaneous injection in an aqeuous solution of 20% dimethylformamide.Bacteria. The bacteria used for animal infections were veterinary and clinical isolates previously found to exhibit susceptibility in vitro to zidovudine and the reference antimicrobial agents used in this study. E. coli P855, used for the mouse systemic infection studies, is a clone from E. coli CN348 (isolated from a sick calf) maintained in the Well-* Corresponding author.come Research Laboratories strain collection. E. coli J96 was used for the mouse ascendin...

Functional characterization of a H+/nucleoside co‐transporter (CaCNT) from Candida albicans, a fungal member of the concentrative nucleoside transporter (CNT) family of membrane proteins

“…Infectious complications due to Candida species are frequent in the clinical care of a variety of immunocompromised individuals, such as organ transplant recipients, AIDS and cancer patients and the elderly (Walsh and Groll, 1999;Garber, 2001). Some human antineoplastic and antiviral nucleoside drugs have ancillary benefits as antibacterial agents (Friedman, 1982;Keith et al, 1989;Monno et al, 1997) and the same may also be possible in the case of fungal infections.…”

Intracellular activity of zidovudine (3'-azido-3'-deoxythymidine, AZT) against Salmonella typhimurium in the macrophage cell line J774-2

“…AZT is also active against enterobacteria such as Escherichia coli and Salmonella and Klebsiella species, but it is not active against Pseudomonas aeruginosa, gram-positive cocci, and Listenia and Mycobacteria species (3,8). As in HIV replication, incorporation of azidothymidylate into a growing DNA strand in the bacteria terminates DNA elongation, inhibiting DNA synthesis (3,7,8,11,13).…”

“…As in HIV replication, incorporation of azidothymidylate into a growing DNA strand in the bacteria terminates DNA elongation, inhibiting DNA synthesis (3,7,8,11,13). AZTresistant bacteria have been isolated from the stools of HIV patients receiving AZT (12).…”

Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae

“…Interestingly, this spontaneous mutation rate did not undermine successful AZT monotherapy in highinoculum, E. coli, systemic calf or mouse pyelonephritis infection models. 48 Additionally, AZT treatment is correlated with a significant reduction in Salmonella relapses among HIV-infected patients, 49 further supporting the hypothesis that development of resistance in vitro does not necessarily preclude AZT efficacy in vivo and the potential for a significant antibacterial effect in humans. PK parameters previously observed for AZT relative to the MIC values (calculated using complete inhibition rather than trailing endpoint inhibition) determined in our survey of carbapenem-resistant strains (MIC 50 = 4) suggest the potential for treatment efficacy.…”